van Vlijmen Herman W T, Karplus Martin
Computational Drug Design Group, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
J Mol Biol. 2005 Jul 15;350(3):528-42. doi: 10.1016/j.jmb.2005.03.028. Epub 2005 Apr 7.
The study of the dynamics and thermodynamics of small icosahedral virus capsids is an active field of research. Normal mode analysis is one of the computational tools that can provide important insights into the conformational changes of the virus associated with cell entry or caused by changing of the physicochemical environment. Normal mode analysis of virus capsids has been limited due to the size of these systems, which often exceed 50,000 residues. Here we present the first normal mode calculation with full dihedral flexibility of several virus capsids, including poliovirus, rhinovirus, and cowpea chlorotic mottle virus. The calculations were made possible by applying group theoretical methods, which greatly simplified the calculations without any approximation beyond the all-atom force field representations in general use for smaller protein systems. Since a full Cartesian basis set was too large to be handled by the available computer memory, we used a basis set that includes all internal dihedral angles of the system with the exception of the peptide bonds, which were assumed rigid. The fluctuations of the normal modes are shown to correlate well with crystallographic temperature factors. The motions of the first several normal modes of each symmetry type are described. A hinge bending motion in poliovirus was found that may be involved in the mechanism by which bound small molecules inhibit conformational changes of the capsid. Fully flexible normal mode calculations of virus capsids are expected to increase our understanding of virus dynamics and thermodynamics, and can be useful in the refinement of cryo-electron microscopy structures of viruses.
小二十面体病毒衣壳的动力学和热力学研究是一个活跃的研究领域。简正模式分析是一种计算工具，它可以为与病毒进入细胞相关或由物理化学环境变化引起的病毒构象变化提供重要见解。由于这些系统的规模往往超过50000个残基，病毒衣壳的简正模式分析受到了限制。在此，我们展示了首次对包括脊髓灰质炎病毒、鼻病毒和豇豆花叶病毒在内的几种病毒衣壳进行的具有完全二面角灵活性的简正模式计算。通过应用群论方法使计算成为可能，该方法大大简化了计算，且除了通常用于较小蛋白质系统的全原子力场表示外没有任何近似。由于完整的笛卡尔基组太大，现有计算机内存无法处理，我们使用了一个基组，该基组包括系统的所有内部二面角，但肽键除外，肽键被假定为刚性。结果表明简正模式的波动与晶体学温度因子有很好的相关性。描述了每种对称类型的前几个简正模式的运动。在脊髓灰质炎病毒中发现了一种铰链弯曲运动，它可能参与了结合的小分子抑制衣壳构象变化的机制。病毒衣壳的完全灵活简正模式计算有望增进我们对病毒动力学和热力学的理解，并可用于改进病毒的冷冻电子显微镜结构。
